International immunopharmacology · 2026
Benzoylpaeoniflorin regulates macrophage polarization via the RNF31-DPEP2 axis to ameliorate intestinal mucosal barrier damage in ulcerative colitis.
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Yang Zhouyu, Li Ke, Li Xinru, Zhong Pei, Hu Yuqian, Yao Xin
Аннотация
BACKGROUND: Targeting macrophage polarization to restore immunological balance is a promising treatment strategy for ulcerative colitis (UC). This study aims to explore the preventive effects of benzoylpaeoniflorin (BPF) for UC and to elucidate the underlying mechanisms.
METHODS: Dextran sulfate sodium (DSS) was used to induce UC in mice, and BPF was administered simultaneously. Lipopolysaccharide (LPS)-stimulated RAW264.7 cells were used to model M1 macrophage polarization skewing, with BPF treatment applied.
RESULTS: BPF improved DSS-induced colitis in mice, reduced M1 macrophage polarization, but significantly promoted M2 macrophage polarization in colonic tissues. After clearing macrophages in UC mice using clodronate disodium liposomes, BPF failed to further ameliorate UC progression in DSS + Mø-/- mice, indicating that macrophages are required for the protective effects of BPF against UC. Proteomics and in vitro/in vivo experiments further revealed that LPS treatment downregulated dipeptidase-2 (DPEP2) expression, while BPF treatment upregulated it. The promoting effect of BPF on DPEP2 expression is achieved by targeting RING finger protein 31 (RNF31) to hinder the binding of RNF31 to DPEP2, thereby inhibiting the ubiquitination and degradation of DPEP2 mediated by RNF31, and inhibiting the activation of the NF-κB signaling pathway. Moreover, DPEP2 knockdown or RNF31 overexpression neutralized the promoting effect of BPF on M2 polarization and its inhibitory effect on M1 polarization. Notably, BPF's therapeutic benefits in UC mice were abolished by DPEP2 knockdown.
CONCLUSION: BPF regulates macrophage polarization by modulating the RNF31-DPEP2-NF-κB axis, thereby ameliorating intestinal mucosal barrier damage in UC.
METHODS: Dextran sulfate sodium (DSS) was used to induce UC in mice, and BPF was administered simultaneously. Lipopolysaccharide (LPS)-stimulated RAW264.7 cells were used to model M1 macrophage polarization skewing, with BPF treatment applied.
RESULTS: BPF improved DSS-induced colitis in mice, reduced M1 macrophage polarization, but significantly promoted M2 macrophage polarization in colonic tissues. After clearing macrophages in UC mice using clodronate disodium liposomes, BPF failed to further ameliorate UC progression in DSS + Mø-/- mice, indicating that macrophages are required for the protective effects of BPF against UC. Proteomics and in vitro/in vivo experiments further revealed that LPS treatment downregulated dipeptidase-2 (DPEP2) expression, while BPF treatment upregulated it. The promoting effect of BPF on DPEP2 expression is achieved by targeting RING finger protein 31 (RNF31) to hinder the binding of RNF31 to DPEP2, thereby inhibiting the ubiquitination and degradation of DPEP2 mediated by RNF31, and inhibiting the activation of the NF-κB signaling pathway. Moreover, DPEP2 knockdown or RNF31 overexpression neutralized the promoting effect of BPF on M2 polarization and its inhibitory effect on M1 polarization. Notably, BPF's therapeutic benefits in UC mice were abolished by DPEP2 knockdown.
CONCLUSION: BPF regulates macrophage polarization by modulating the RNF31-DPEP2-NF-κB axis, thereby ameliorating intestinal mucosal barrier damage in UC.